This project is aimed at examining the activity of caspase enzymes and the presence of apoptosis in human brain tissue from AIDS patients and in transgenic mouse models of HIV infection. The first phase of the project will involve examining the activity of caspase enzymes in neuropathologic specimens from HIV-infected patients. The experiments will also employ transgenic mice which express gp120 in CNS tissue. It has previously been demonstrated that expression of the gp120 transgene produces neurologic injury similar to that seen in HIV infected patients. Transgenic mice will be used to study how gP120 affects caspase enzyme activity and apoptosis at several developmental time points. Cell type specific markers will be employed to determine if neurons, glia or microglia are the primary target of gp120-induced apoptosis. Experiments are also planned which involve two different strategies (transgenic and pharmacologic) aimed at inhibiting caspase enzyme activity to determine if this intervention may prevent apoptosis and neural injury in gp120 transgenic mice. The experiments aim to advance the understanding of the mechanisms of HIV-induced neural injury, and thereby provide insight into new pharmacologic strategies for preventing neurologic dysfunction in patients infected with HIV.